FcRn-dependent IgG accumulation in adipose tissue unmasks obesity pathophysiology

Lexiang Yu, Yong Xiao Yang, Zhen Gong, Qianfen Wan, Yifei Du, Qiuzhong Zhou, Yang Xiao, Tarik Zahr, Zhaobin Wang, Zhewei Yu, Kangkang Yang, Jinyang Geng, Susan K. Fried, Jing Li, Rebecca A. Haeusler, Kam W. Leong, Lin Bai, Yingjie Wu, Lei Sun, Pan WangBao Ting Zhu, Liheng Wang, Li Qiang

Research output: Contribution to journalArticlepeer-review

Abstract

Immunoglobulin G (IgG) is traditionally recognized as a plasma protein that neutralizes antigens for immune defense. However, our research demonstrates that IgG predominantly accumulates in adipose tissue during obesity development, triggering insulin resistance and macrophage infiltration. This accumulation is governed by neonatal Fc receptor (FcRn)-dependent recycling, orchestrated in adipose progenitor cells and macrophages during the early and late stages of diet-induced obesity (DIO), respectively. Targeting FcRn abolished IgG accumulation and rectified insulin resistance and metabolic degeneration in DIO. By integrating artificial intelligence (AI) modeling with in vivo and in vitro experimental models, we unexpectedly uncovered an interaction between IgG's Fc-CH3 domain and the insulin receptor's ectodomain. This interaction hinders insulin binding, consequently obstructing insulin signaling and adipocyte functions. These findings unveil adipose IgG accumulation as a driving force in obesity pathophysiology, providing a novel therapeutic strategy to tackle metabolic dysfunctions.

Original languageEnglish
JournalCell Metabolism
DOIs
StateAccepted/In press - 2025

Keywords

  • adipose tissue remodeling
  • FcRn
  • IgG
  • insulin receptor
  • insulin resistance
  • obesity

Fingerprint

Dive into the research topics of 'FcRn-dependent IgG accumulation in adipose tissue unmasks obesity pathophysiology'. Together they form a unique fingerprint.

Cite this